An Appraisal On Diclofenac and Its Undesirable Effects: From Pain Relief to Systemic Damage

Poduri Lakshmi Lohita Priya*, Syed Tehameem Afzal, Sheik Arshiya Anjum

PharmD Vikas Institute of Pharmaceutical Sciences, Rajahmundry

*Correspondence: lohithapoduri@gmail.com

DOI: https://doi.org/10.71431/IJRPAS.2025.4702  

INTRODUCTION

Diclofenac, which is a phenyl acetic acid derivative holding a carboxylic acid functional group. It is a potent inhibitor of cyclooxygenase enzyme activity and may also associated with lipoxygenase enzyme activity and the precursor to release and reuptake of arachidonic acid [1]. It was synthesized Alfred Sallman and Rudolf Pfister and first introduced by Ciba-Geigy (now Novartis AG, Basel, Switzerland) [2].

It is available in different administered forms like orally, rectally, intramuscularly. The dose adjustments cannot be required in the elder people or the people with renal and hepatic problems though careful monitoring is required [3].

MECHANISM OF ACTION: -

Diclofenac sodium works by reducing the release of arachidonic acid, increasing the absorption of arachidonic acid, and strongly inhibiting cyclo-oxygenase. A dual inhibitory action on the cyclo-oxygenase and lipoxygenase pathways is the outcome [4]. The suppression of cyclooxygenase (COX) enzymes is the main way that diclofenac sodium works. COX-1 and COX-2 are the two primary isoforms of the COX enzyme. These enzymes oversee converting arachidonic acid into prostaglandins, which are lipid molecules that are essential for the experience of pain, inflammation, and fever [5].

PHARMACOKINETICS: -

Diclofenac is rapidly and fully absorbed when taken orally. Plasma albumin is strongly attracted to diclofenac. The diclofenac area under the plasma concentration-time curve (AUC) is proportionate to the dose for oral dosages between 25 and 150 mg [6]. Following significant hepatic metabolism, diclofenac is bio transformed into conjugated metabolites (glycoconjugate and sulphate metabolites) and then eliminated in urine.29 While 3-OH and 5-OH diclofenac minor metabolites are subject to glucuronidation and sulfation, 4-hydroxy (OH) diclofenac is the principal metabolite of diclofenac [7].

THERAPEUTIC USES: -

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) used to treat mild-to-moderate pain and to lessen inflammation, stiffness, oedema, and joint pain related to arthritis (such as rheumatoid arthritis or osteoarthritis). This drug doesn't cure arthritis; it just helps you while you use it. Additionally, ankylosing spondylitis, a kind of arthritis that affects the joints in the spine, and unpleasant conditions like menstruation cramps are treated with this medicine. Diclofenac can also be used to treat acute migraine attacks in adults, whether they include aura. It won't lessen the frequency or prevent migraine attacks [8].

ADVERSE EFFECTS: -

There are some potentially harmful adverse effects of diclofenac. Some of these, such hemolytic anemia and stomach mucosal damage, are rather prevalent. Others, such as thrombocytopenia, are very rare [9].

Diclofenac's negative effects are determined by both logical and irrational use factors.

EFFECT ON CARDIOVASCULAR SYSTEM

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic and anti-inflammatory properties, but their cardiovascular effects remain a topic of concern. This study evaluated the acute effects of diclofenac on cardiac function, coronary autoregulation, and oxidative stress biomarkers in isolated rat hearts.

Impact on the Contractility of the Heart

The maximum and minimum rates of left ventricular (LV) pressure development were used to measure cardiac contractility. The findings showed that at greater coronary perfusion pressure (CPP) levels, diclofenac markedly decreased myocardial contractility. This is consistent with earlier research showing that diclofenac reduces cardiac contractility and excitability, presumably because of its inhibitory effects on cardiac muscle cell Na+ and L-type Ca2+ currents.

Effect on Coronary Flow and Heart Rate

At higher CPP levels, diclofenac caused a reduction in heart rate (HR) and coronary flow (CF). It has been shown to affect HR and the length of action potentials. Nevertheless, prior research indicates that long-term use of therapeutic dosages of diclofenac does not raise the incidence of arrhythmia in healthy hearts, suggesting that the observed effects may be specific to acute administration.

Selectivity of Cyclooxygenase and the Risk of Cardiovascular Disease

Diclofenac has higher selectivity for COX-2 despite being categorized as a nonselective NSAID. Its effects on the heart may be explained in part by this distinction. Interestingly, meta-analyses have shown that diclofenac is more likely than other NSAIDs to cause vascular events.

Generation of ROS and Oxidative Stress

In contrast to what was anticipated, oxidative stress indicators did not significantly alter after using diclofenac. Most oxidative stress markers were unchanged by diclofenac, even though it reduced nitrite plasma levels, which suggests decreased nitric oxide (NO) bioavailability and possible vasoconstriction. Diclofenac's possible antioxidant qualities as a reactive oxygen species (ROS) scavenger may help explain the reported effects, even if some research indicates that it causes oxidative stress in vascular tissues.

According to the current research, diclofenac significantly impairs cardiac function, especially by decreasing myocardial contractility. At higher CPP values, it also lowers CF and HR. Nevertheless, oxidative stress does not seem to be the mechanism behind its cardiac effects. These results shed more information on diclofenac's cardiovascular safety profile and emphasize the need for caution when administering medication to patients who already have heart issues.[10]

 EFFECT ON GASTROINTESTINAL TRACT: -

NSAID-Induced Damage to the Gastric Mucosa: A Two-Pronged Theory

NSAIDs have had varying impacts on mucosal blood flow; some have increased it, while others have decreased it. GI bleeding and ulceration may be exacerbated by decreased mucosal blood flow. It has been demonstrated that aspirin increases cell loss and delays epithelial regeneration, which can result in mucosal erosions, ulcers, and gastrointestinal bleeding.

Prostaglandin Inhibition and Gastric Damage

NSAIDs primarily exert their effects by inhibiting cyclooxygenase (COX) enzymes, particularly COX-1, which is crucial for maintaining gastric mucosal defense. Diclofenac, a potent COX inhibitor, significantly reduces prostaglandin levels, weakening the mucosal barrier. This disruption increases the stomach’s vulnerability to acid-induced injury, ulcer formation, and GI bleeding.

Effect on Cellular Regeneration and Mucosal Blood Flow

NSAIDs have the potential to interfere with mucosal blood flow, which is essential for preserving stomach integrity. Some NSAIDs, like diclofenac, have been shown to decrease blood flow, whereas others have been shown to enhance it. This can result in ischemia, making the patient more vulnerable to ulcers and gastrointestinal bleeding. Damage is exacerbated by reduced mucosal perfusion, which hinders the stomach's capacity to heal itself.

It has been demonstrated that aspirin increases cell loss and delays epithelial regeneration, which can result in mucosal erosions and ulcers. Other NSAIDs, such as diclofenac, which suppresses regular cell metabolism and postpones tissue healing, may also have this impact.

Inhibition of Prostaglandins and Gastric Damage

Inhibiting cyclooxygenase (COX) enzymes, especially COX-1, which is essential for preserving stomach mucosal defense, is the principal way that NSAIDs work. Diclofenac, a strong COX inhibitor, weakens the mucosal barrier by drastically lowering prostaglandin levels. This disturbance makes the stomach more susceptible to GI bleeding, ulcer development, and acid-induced damage.

NSAID-induced stomach injury is largely caused by prostaglandin inhibition; however, some research indicates that mucosal damage cannot be entirely explained by prostaglandin suppression alone. Individual differences in how they react to NSAIDs suggest that stomach injury is also caused by other mechanisms, such as direct irritation of the mucosa.

NSAIDs' Systemic and Topical Effects

Both systemic and topical routes are used by NSAIDs, such as diclofenac, to produce gastrointestinal damage. Cellular damage results from increased membrane permeability caused by direct mucosal interaction with acidic NSAIDs. The drug's acidity, velocity of absorption, and capacity to permeate stomach epithelial cells all affect how severe this damage is.

It has been demonstrated that enteric-coated and buffered NSAID formulations lessen mucosal irritation, highlighting the significance of direct contact harm. Even with parenteral NSAID therapy, stomach damage has been reported, therefore systemic prostaglandin inhibition is still crucial.

Both direct epithelium toxicity and prostaglandin suppression contribute to the dual-injury process that causes NSAID-induced GI bleeding and ulceration. As a strong prostaglandin inhibitor, diclofenac carries a significant risk of damaging the stomach mucosa. By comprehending these pathways, safer NSAID treatments and gastroprotective measures to lessen their negative effects can be developed.[11]

EFFECT ON HEPATIC SYSTEM

Histopathological Characteristics of Liver Damage Caused by Diclofenac

When liver biopsy or autopsy materials from patients with diclofenac-induced liver injury are examined histopathological, the results frequently fall short of offering conclusive information on the underlying causes. This restriction results from the infrequent availability of liver samples, which in the few instances that they are, usually show severe stages of damage that are frequently linked to drug-induced liver failure. Hepatic necrosis, which is often diffuse but can manifest in different ways based on patient-specific variables, is the defining pathological hallmark seen.

The Possible Causes of Diclofenac's Hepatotoxicity

Drug-related variables, patient-specific vulnerability, and underlying illness states interact intricately to cause idiosyncratic drug-induced liver damage (DILI). New experimental studies have clarified important toxicokinetic and toxicodynamic processes behind the hepatotoxicity of diclofenac:

Diclofenac is extensively metabolized in the liver, mostly by cytochrome P450 enzymes (CYP2C9 and CYP3A4), which results in the production of reactive intermediates like acyl glucuronides and quinone imines. Covalent bonds between these metabolites and cellular macromolecules can result in immune-mediated damage, mitochondrial malfunction, and oxidative stress.

Mitochondrial Toxicity and ATP Depletion: Diclofenac impairs oxidative phosphorylation, which damages mitochondrial function and causes ATP depletion and hepatocyte death. The development of hepatocellular necrosis is significantly influenced by the mitochondrial permeability transition (MPT). Hepatic bile salt export pumps (BSEP) can be inhibited by diclofenac and its metabolites, which might cause cholestatic liver damage in certain situations. The range of clinical manifestations, from mixed or cholestatic liver injury to hepatocellular necrosis, may be explained by this mechanism.[12]

EFFECT ON RENAL SYSTEM: -

Like all NSAIDs, diclofenac stops prostaglandin formation by blocking cyclooxygenase (COX) enzymes. Prostaglandin metabolism, which controls renal blood flow, glomerular filtration, renin release, ion transport, and water metabolism, is largely dependent on the kidney. Renal impairment brought on by prostaglandin inhibition may result in ischemia and structural damage.

Tubular atrophy and necrosis result from decreased renal blood flow brought on by diclofenac-induced afferent arteriole constriction. Studies showing renal failure and vacuolar degeneration of the proximal tubules in those using NSAIDs lend credence to this. Furthermore, cell degeneration and structural loss cause proximal tubule dilatation, which results in the temporary loss of renal cells.

In the renal cortex and medulla, diclofenac also causes interstitial nephritis, presumably because of COX inhibition that shifts arachidonic acid metabolism towards the lipoxygenase route. Renal inflammation and tissue damage are sustained because of the recruitment of T-lymphocytes by inflammatory eicosanoids.[13]

DISCUSSION

Diclofenac poses a greater risk of gastrointestinal bleeding, ulceration, and hepatotoxicity compared to ibuprofen [14]. Regulators have issued warnings since it is also associated with a markedly increased risk of cardiovascular events like heart attacks and strokes [15]. Ibuprofen, on the other hand, is usually seen as safer having a lower incidence of these side effects, especially at lower doses, which makes it a preferable choice for individuals with liver or cardiovascular issues.[16] According to a study that was published in BMC Zoology, diclofenac was more nephrotoxic and hepatotoxic than ibuprofen and paracetamol. Higher toxicity was indicated by the considerable changes in liver enzymes and renal function indicators caused by diclofenac. The results emphasize that diclofenac should be used with caution, particularly in patients who have liver or kidney problems.[17]

CONCLUSION

Like other nonsteroidal anti-inflammatory drugs, diclofenac primarily works by blocking the cyclooxygenase (COX) enzymes, which lowers the production of prostaglandins. This mechanism leads to gastrointestinal (GI) problems like ulceration and bleeding, even though it has anti-inflammatory, analgesic, and antipyretic effects. Prostaglandin inhibition also alters vascular and renal balance, which may have negative systemic implications. The effects on other organs and the gastrointestinal tract emphasize the need for careful use, especially in those who are more susceptible to NSAID-related problems.

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